Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular rate-limiting enzyme in the metabolism of tryptophan along the kynurenine pathway, subsequently mediating the immune response; however, the role of IDO1 in liver fibrosis and cirrhosis is still unclear. In this study, we investigated the role of IDO1 in the development of hepatic fibrosis and cirrhosis. Patients with hepatitis B virus-induced cirrhosis and healthy volunteers were enrolled. For animals, carbon tetrachloride (CCl4) was used to establish liver fibrosis in wild-type and IDO1 knockout mice. Additionally, an IDO1 inhibitor (1-methyl-D-tryptophan) was administered to WT fibrosis mice. Liver lesions were positively correlated with serum IDO1 levels in both the clinical subjects and hepatic fibrosis mice. A positive correlation between serum IDO1 levels and liver stiffness values was found in the cirrhosis patients. Notably, IDO1 knockout mice were protected from CCl4-induced liver fibrosis, as reflected by unchanged serum alanine transaminase and aspartate transaminase levels and lower collagen deposition, α-smooth muscle actin expression and apoptotic cell death rates. On the other hand, tryptophan 2,3-dioxygenase (TDO), another systemic tryptophan metabolism enzyme, exhibited a compensatory increase as a result of IDO1 deficiency. Moreover, hepatic interleukin-17a, a characteristic cytokine of T helper 17 (Th17) cells, and downstream cytokines’ mRNA levels showed lower expression in the IDO1–/– model mice. IDO1 appears to be a potential hallmark of liver lesions, and its deficiency protects mice from CCl4-induced fibrosis mediated by Th17 cells down-regulation and TDO compensation.
Highlights
Liver fibrosis is a wound-healing process elicited by various toxic injuries, including viruses, alcohol and fat accumulation, and it is the final common pathway of almost all chronic liver diseases [1]
We first conducted clinical trials on patients with hepatitis B virus (HBV)-induced cirrhosis to investigate whether the serum level of IDO1 would change compared with healthy volunteers (HVs) (Figure 1A)
With Pearson’s linear correlation tests, we found that the serum IDO1 level was positively correlated with serum γ-glutamyl transferase (GGT), direct bilirubin (DB) and total bile acid (TBA) levels (Figure 1F)
Summary
Liver fibrosis is a wound-healing process elicited by various toxic injuries, including viruses, alcohol and fat accumulation, and it is the final common pathway of almost all chronic liver diseases [1]. Liver fibrosis mainly results from liver injurymediated inflammation and activation of hepatic stellate cells (HSCs). Recent evidence indicates that activation of the immune system is closely related to liver fibrosis [5]. T cell-mediated immune injury plays an important role in the development of chronic liver disease, which is induced by viruses, parasites and chemicals. In patients with chronic liver disease, CD4+ T cells decrease, while CD8+ T cells increase. Interleukin 17a (IL-17a), the characteristic cytokine of Th17 cells, is a known hepatic fibrosis inducer that mediates ECM remodelling [8,9,10]
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